A green ultrasound-driven strategy for the design and discovery of embelin-fused phenazine antibacterials: synthesis, docking, and ADMET evaluation
摘要
The escalating crisis of antimicrobial resistance demands the vital development of novel antibacterial agents with advanced mechanisms of action. This study reports the design and efficient, eco-friendly aqueous-mediated ultrasound-assisted sustainable synthesis of molecular hybrids (3a–3e) by conjugating embelin, extracted from berries of Embelia ribes (E. ribes), with phenazine nuclei, thereby exhibiting their inherent antibacterial activity. This research provided a green synthesis that was proficiently accomplished via an ultrasound-mediated methodology, offering significant advantages, including aqueous medium, shorter reaction times, higher yields, and greener chemical protocols compared to conventional methods. The synthesized derivatives were characterized using Fourier Transform Infrared Spectroscopy (FT-IR), Proton Nuclear Magnetic Resonance (1H-NMR), and High-Resolution Mass Spectroscopy (HR-MS). The synthesized compounds 3a-3e and the standard antibiotic (Ciprofloxacin) were evaluated for their in vitro antibacterial activity against the Gram-positive Staphylococcus aureus (S. aureus) (Microbial Type Culture Collection and Gene Bank) (MTCC 7443), Bacillus cereus (B. cereus)(MTCC 8750), and Gram-negative Escherichia coli (E. coli) (MTCC 724) bacteria. Several compounds 3b, 3c, 3d, and 3e demonstrated more potent and broad-spectrum antibacterial efficacy compared to the standard antibiotic. Across all three bacterial strains, the compounds exhibited inhibitory effects in the concentration range of 4–10 mg/mL. To elucidate the potential mechanism of action, molecular docking (in silico) studies were performed using AutoDock 4.2.0 against the 5-lipoxygenase enzyme (5-LOX) (PDB ID: 3V99), revealing strong binding affinities and favorable interactions within the active site conformation of synthesized compounds 3a-3e. Derivative 3b shows the highest binding energy of 7.97 Kcal/mol, and the lowest inhibition constant (1.43) than the standard drug (Zileuton) and all derivatives. The compounds 3a (binding energy 7.46 Kcal/mol), 3d (binding energy 7.66 Kcal/mol), and 3e (binding energy 7.53 Kcal/mol) have binding energies greater than 7.11 Kcal/mol of the standard drug. The stable complex formation suggests its good competitiveness as an inhibitor of the 5-LOX enzyme. Furthermore, comprehensive in silico ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) predictions indicated that all synthesized compounds (3a-3e) exhibit promising pharmacokinetic and drug-likeness properties. Collectively, the antibacterial, molecular docking, and ADMET studies identify that the synthesized compounds (3a-3e) could serve as potential inhibitors of the 5-LOX enzyme and promising antibacterial drug candidates.
Graphical abstract